The texaphyrins are aromatic pentadentate macrocyclic "expanded porphyrins" that have been found to be useful as MRI contrast agents and in photodynamic therapy (PDT). Texaphyrin is considered as being an aromatic oenzannulene containing both 18.pi.- and 22.pi.-electron delocalization pathways. See, e.g., Sessler, J. L. et al., Accounts of Chemical Research, 1994, 27:43. It has been determined that the sites of localization of the texaphyrins in vivo include neoplastic tissue and atheromatous plaque. This selective biolocalization underlies many of the pharmaceutical applications of texaphyrins, i.e., in the diagnosis and treatment of cancers and cardiovascular abnormalities. It has also been shown that texaphyrins can act as a radiation sensitizer in the radiation treatment of cancers and as a chemosensitizer to increase the activity of certain chemotherapy drugs.
Conjugates of texaphyrins with "site-directing groups" such as oligonucleotides and estrogen have been prepared. These site-directing groups are chemical entities that can recognize, through non-covalent interactions, a specific receptor molecule. Covalent attachment to such a site-directing group would be expected to direct the texaphyrin complex to the location of the specific receptor molecule recognized.
Texaphyrins, methods of preparation, and uses have been described in, for example, U.S. Pat. Nos. 4,935,498; 5,252,720; 5,457,183; 5,559,207; 5,565,552; 5,567,687; 5,587,371; 5,594,136; and 5,714,328; and International PCT Publication WO 97/26915; all of which are incorporated herein by reference.
Many of the most prevalent forms of human cancer resist effective chemotherapeutic intervention. Some tumor populations, especially adrenal, colon, jejunal, kidney and liver carcinomas, appear to have drug-resistant cells at the outset of treatment (Barrows, L. R., in Remington: The Science and Practice of Pharmacy, Mack Pub. Co., Easton, Pa., 1995, p. 1249). In other cases, resistance appears to be acquired in much the same way as microbial resistance: a resistance-conferring genetic change occurs during treatment; the resistant daughter cells then proliferate in the environment of the drug. Whatever the cause, resistance often terminates the usefulness of an antineoplastic drug.
Cisplatin ("cis-Pt"; diammine(dichloro)platinum(II)) was first synthesized by Peyrone in 1844; however, the tumor-inhibiting properties of the compound were not recognized until 1969 by Rosenberg (Rosenberg, B., et al., Nature, 1969, 222:385-386). Today, cisplatin has become one of the most frequently used anticancer drugs. It is prescribed for the treatment of testicular and ovarian cancer and has recently been shown to be effective against cervical, bladder, and head/neck tumors. The generally accepted mechanism for its antitumor activity involves intrastrand coordination of [Pt(NH.sub.3).sub.2 (H.sub.2 O).sub.n Cl.sub.2-n ] (formed after intracellular hydrolysis of cis-Pt) to cellular DNA, preferentially at the N.sup.7 atoms of two adjacent guanine bases, thus blocking DNA replication.
Although cisplatin is a widely used drug, there are several drawbacks associated with its treatment regime and activity. Primarily, the platinum complex is poorly soluble in saline, and patients can experience severe toxic side effects to treatment, including nausea, hearing loss, vomiting, loss of sensation in hands, and renal toxicity. Cisplatin acts unspecifically and damages all rapidly growing body tissues as well as the tumor. Additionally, cisplatin can be used for only a narrow range of tumors and some tumor cell lines may develop resistance to the platinum drug.
Efforts to find better cytotoxic agents have involved chemically linking a cis-Pt center, or an analogous platinum coordination complex, to a biocompatible carrier that will improve its ability to target certain organs, tissues, or tumor cells. Specifically, coordination inter alia to amino phosphonic acids (Bloemink, M. J. et al. Inorg. Chem., 1994, 33:1127-1132), ferrocene (Rosenfeld, A. et al. Inorg. Chim. Acta, 1992, 201:219-221), and porphyrins (Brunner, H. et al. Chem. Ber., 1995, 128:173-181; Chem. Ber., 1994, 127:2141-2149) has been tried, but with limited success. Cis-Pt has also been linked to agents that target cellular DNA, namely intercalating acridine chromophores (Lee, H. H. et al. J. Med. Chem., 1992, 35:2983-2987; Wickham, G. et al. In Platinum and Other Metal Coordination Complexes in Cancer Chemotherapy, S. B. Howell, Ed., Plenum Press, N.Y., 1991, pp. 51-60; Mikata, Y. et al. Bioorg. Med. Chem. Lett., 1997, 7:1083-1086; Bowler, B. E. et al. J. Am. Chem. Soc., 1989, 111:1299-1306). Alternatively, cisplatin complexes (containing co-ligands that may offer an additive or synergistic effect to disease treatment have also been synthesized. These systems may offer additional chemotherapeutic capabilities (Hollis, L. S. et al. J. Med. Chem., 1990, 33:105-111) or may enhance other types of treatment. Nitroimidazoles, which are radiosensitizers, have been complexed with cis-Pt-type complexes in order to enable radiation therapy to be pursued in conjunction with chemotherapy (Farrell, N., and Skov, K. A. J. Chem. Soc. Chem. Commun., 1987, 1043-1044). Complexation with porphyrins has also been considered in this context (Brunner, H. et al., supra).
Doxorubicin (adriamycin) is another widely used drug in the battle against cancer. It is an anthracycline antibiotic that binds to DNA and inhibits nucleic acid synthesis, inhibits topoisomerase II and produces oxygen radicals. Doxorubicin has the widest antineoplastic spectrum and usefulness of the antineoplastic drugs (Barrows, L. R., in Remington: The Science and Practice of Pharmacy, Mack Publ. Co., Easton, Pa., 1995, p. 1249). As with other chemotherapeutic drugs, the anthracyclines cause serious, including toxic, side effects in patients, including bone marrow suppression and mucositis, which are dose limiting; hair loss; extravasation, which leads to severe local reaction; cumulative cardiomyopathy that can lead to congestive heart failure; and cardiac toxicity.
Taxol (Paclitaxel), a complex diterpenoid isolated in small yields from the bark of the western yew Taxus brevifolia, and its semisynthetic derivative docetaxel (Taxotere, Rhone-Poulenc) constitute one of the most potent drugs in cancer chemotherapy. Paclitaxel has been approved by FDA for treatment of ovarian and breast cancer and is also showing promise in the treatment of lung, skin, and head/neck cancers.
Unfortunately, the clinical utility of taxoid drugs (i.e., Paclitaxel, Docetaxel) is severely constrained by their cost, limited bioavailability (a direct reflection of low iaqueous solubility), and the development of multiresistant cells. To date, considerable effort has indeed been devoted to the problem of improving the water solubility of taxol using such classic strategies as prodrug masking and conjugate construction. However, it is fair to say that the problem is far from solved. Indeed, there are several significant challenges related to the design of successful taxol prodrugs and conjugates. First, the product produced, whether a prodrug or a conjugate, should be at least partially water soluble (to facilitate administration). However, it needs to retain sufficient lipophilicity such that is not cleared through the kidneys too quickly. Second, and perhaps more seriously, it must retain the basic biological character of taxol, notably the ability to bind to the surprisingly selective receptor on microtubules.